beta-carotene and Carcinoma--Non-Small-Cell-Lung

Previous observational studies have suggested that the effect of diet-derived circulating micronutrient concentrations on lung cancer (LC) risk is controversial. We conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between circulating micronutrient concentrations and the overall risk of LC and three LC subtypes (namely lung adenocarcinoma (LA), squamous cell lung cancer (SqCLC), and small cell lung cancer (SCLC)). The instrumental variables (IVs) of 11 micronutrients (beta-carotene, calcium, copper, folate, lycopene, magnesium, phosphorus, retinol, selenium, zinc, and vitamin B6) were screened from the published genome-wide association studies (GWAS). Summary statistics related to LC and its subtypes came from the largest meta-analysis, including 29,266 cases and 56,450 controls. Inverse-variance weighted (IVW) method is used as the main MR analysis, and the sensitivity analysis is carried out to ensure the MR assumptions. This MR study found suggestive evidence that genetically predicted 6 circulating micronutrient concentrations was correlated with the risk of overall LC (odds ratio (OR): 1.394, 95% confidence interval (CI): 1.041-1.868,

Topics: beta Carotene; Calcium; Carcinoma, Non-Small-Cell Lung; Copper; Genome-Wide Association Study; Humans; Lung Neoplasms; Mendelian Randomization Analysis; Micronutrients; Phosphorus; Polymorphism, Single Nucleotide; Vitamin A; Zinc

Treatment of lung cancer remains frustrating. Most patients with lung cancer are not candidates for curative therapy, and new therapies have not made a substantial impact on survival. Consequently, some clinical investigators have focused their efforts on developing prevention strategies. Chemoprevention, the administration of agents to block or reverse carcinogenesis, is being investigated in ongoing trials. Studies of chemoprevention in lung cancer have included trials to reverse premalignant lesions such as sputum atypia or squamous metaplasia of the bronchial epithelium. Clinical trials of lung cancer prevention have often studied groups of participants with tobacco or asbestos exposure. Other clinical trials are being conducted among patients who have been treated for an early-stage lung cancer. As the result of diffuse epithelial injury, these patients are at very high risk for developing second primary tumors, predominantly in the lungs and upper aerodigestive tract. It is our hope that these studies may establish a new strategy for preventing lung cancer.

Topics: Anticarcinogenic Agents; beta Carotene; Carcinoma, Non-Small-Cell Lung; Carotenoids; Clinical Trials as Topic; Humans; Isotretinoin; Lung Neoplasms; Neoplasms, Second Primary; Precancerous Conditions; Randomized Controlled Trials as Topic

The neutrophil-to-lymphocyte ratio (NLR) is a biomarker that indicates systemic inflammation and can be estimated using array-based DNA methylation data as methylation-derived NLR (mdNLR). We assessed the relationship between prediagnosis mdNLR and lung cancer risk in a nested case-control study in the β-Carotene and Retinol Efficacy Trial (CARET) of individuals at high risk for lung cancer due to heavy smoking or substantial occupational asbestos exposure. We matched 319 incident lung cancer cases to controls based on age at blood draw, smoking, sex, race, asbestos, enrollment year, and time at risk. We computed mdNLR using the ratio of predicted granulocyte and lymphocyte proportions derived from DNA methylation signatures in whole blood collected prior to diagnosis (median 4.4 years in cases). Mean mdNLR was higher in cases than controls (2.06 vs. 1.86,

Topics: Aged; Asbestos; beta Carotene; Carcinoma, Non-Small-Cell Lung; Case-Control Studies; Diterpenes; DNA Methylation; Female; Humans; Inflammation; Lung Neoplasms; Lymphocyte Count; Lymphocytes; Male; Middle Aged; Neutrophils; Occupational Exposure; Oligonucleotide Array Sequence Analysis; Retinyl Esters; Risk Factors; Smokers; Smoking; Vitamin A

In vitro and animal studies suggest that antitumor effect of chemotherapeutic agents may be enhanced by antioxidants. Therefore, we initiated a clinical study to test the efficacy of high-dose multiple antioxidants (vitamins C, E and beta carotene) as an adjunct to chemotherapy (paclitaxel and carboplatin) in non-small-cell lung cancer.. 136 patients of stage IIIb and stage IV NSCLC were randomized to receive chemotherapy (paclitaxel and carboplatin) alone (chemotherapy arm, n = 72) or chemotherapy in combination with ascorbic acid 6100 mg/day, dl-alpha-tocopherol (vitamin E) 1050 mg/day and beta-carotene 60 mg/day (combination arm, n = 64). Survival were calculated by the Kaplan-Meier method and compared using the log-rank test.. An overall response rate (RR) of 33% was observed in chemotherapy arm with 24 patients showing a partial response (PR) and none showing a complete response (CR). In combination arm the overall RR was 37% with 24 patients showing PR and two showing CR. The median survival times in chemotherapy arm and combination arm were nine and 11 months respectively. The overall survival (OS) rates in chemotherapy arm and combination arm at one year were 32.9% and 39.1%, and at two years, 11.1% and 15.6% respectively. None of these differences were statistically significant (p = 0.20). Toxicity profiles were similar in both arms.. These results do not support the concern that antioxidants might protect cancer cells from the free radical damage induced by chemotherapy. Larger trials are needed to demonstrate whether high-dose multiple antioxidants in conjunction with chemotherapy increase the response rates and/or survival time in advanced lung cancer.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Ascorbic Acid; beta Carotene; Carcinoma, Non-Small-Cell Lung; Drug Synergism; Female; Humans; Lung Neoplasms; Male; Middle Aged; Survival Analysis; Vitamin E

Preliminary studies have identified pro-surfactant protein B (pro-SFTPB) to be a promising blood biomarker for non-small-cell lung cancer. We conducted a study to determine the independent predictive potential of pro-SFTPB in identifying individuals who are subsequently diagnosed with lung cancer.. Pro-SFTPB levels were measured in 2,485 individuals, who enrolled onto the Pan-Canadian Early Detection of Lung Cancer Study by using plasma sample collected at the baseline visit. Multivariable logistic regression models were used to evaluate the predictive ability of pro-SFTPB in addition to known lung cancer risk factors. Calibration and discrimination were evaluated, the latter by an area under the receiver operating characteristic curve (AUC). External validation was performed with samples collected in the Carotene and Retinol Efficacy Trial (CARET) participants using a case-control study design.. Adjusted for age, sex, body mass index, personal history of cancer, family history of lung cancer, forced expiratory volume in one second percent predicted, average number of cigarettes smoked per day, and smoking duration, pro-SFTPB (log transformed) had an odds ratio of 2.220 (95% CI, 1.727 to 2.853; P < .001). The AUCs of the full model with and without pro-SFTPB were 0.741 (95% CI, 0.696 to 0.783) and 0.669 (95% CI, 0.620 to 0.717; difference in AUC P < .001). In the CARET Study, the use of pro-SFPTB yielded an AUC of 0.683 (95% CI, 0.604 to 0.761).. Pro-SFTPB in plasma is an independent predictor of lung cancer and may be a valuable addition to existing lung cancer risk prediction models.

Topics: Aged; Anticarcinogenic Agents; Area Under Curve; beta Carotene; Biomarkers, Tumor; Canada; Carcinoma, Non-Small-Cell Lung; Case-Control Studies; Early Detection of Cancer; Female; Humans; Logistic Models; Lung Neoplasms; Male; Middle Aged; Multicenter Studies as Topic; Multivariate Analysis; Odds Ratio; Predictive Value of Tests; Protein Precursors; Pulmonary Surfactant-Associated Proteins; Randomized Controlled Trials as Topic; Risk Factors; ROC Curve

The combination of anti-cancer drugs with nutritional factors is a potential strategy for improving the efficacy and decreasing the toxicity of chemotherapy. However, whether nutritional factors enhance the effect of trichostatin A (TSA), a novel anti-cancer drug, is unclear.. We investigated the individual enhancing effect and its possible mechanisms of genistein, daidzein, beta-carotene, retinoic acid, and alpha-tocopherol on the cell-growth-inhibitory effect of TSA in a human lung carcinoma cell line, A549.. A549 cells were incubated with TSA (50 ng/mL) alone or in combination with the various nutritional factors for various times, and cell growth was measured. IMR90 cells, human lung fibroblasts, were also incubated with TSA alone or in combination with genistein or beta-carotene to determine the selectivity of these treatments. In addition, we studied effects on the cell cycle, caspase-3 activity, and DNA damage (by comet assay) in A549 cells.. After treatment for 72 h, 10-microM genistein or beta-carotene significantly enhanced the growth-inhibitory effect of TSA in A549 cells. Daidzein, retinoic acid, and alpha-tocopherol at the same concentration had no significant effect. However, genistein and beta-carotene failed to enhance the cell-growth-arrest effect of TSA in IMR90 cells. Flow cytometric analysis showed that both genistein and beta-carotene significantly increased the TSA-induced apoptosis in A549 cells. Genistein significantly enhanced TSA-induced caspase-3 activity in A549 cells by 34% at 24 h, and the caspase-3 inhibitor partly inhibited the enhancing effect of genistein on TSA-induced apoptosis. beta-Carotene did not significantly affect TSA-induced caspase-3 activity. However, beta-carotene rather than genistein enhanced TSA-induced DNA damage.. Genistein and beta-carotene enhance the cell-growth-arrest effect of TSA on A549 cells. Genistein exerts its effect, at least partly, by increasing caspase-3 activity; whereas beta-carotene may enhance TSA-induced cell death mainly through a caspase-3-independent pathway.

Topics: Antineoplastic Agents; Apoptosis; beta Carotene; Carcinoma, Non-Small-Cell Lung; Caspase 3; Cell Cycle; Cell Division; Cell Line; Cell Line, Tumor; DNA Damage; Drug Interactions; Enzyme Activation; Fibroblasts; Genistein; Humans; Hydroxamic Acids; Lung

Two primary prevention trials unexpectedly showed adverse effects of supplemental beta-carotene on lung cancer incidence in cigarette smokers. To elucidate the molecular mechanisms that might underlie these effects, we studied the immunohistochemical expression of cytochrome P450 1A1, 1A2, and 2E1, retinoic acid receptor beta, activated protein-1 elements, cyclin D1, and Ki67 in lung tumors and, when available, adjacent normal tissues obtained from incident cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Archival lung tissue was available from 52 men randomized to receive 20 mg of beta-carotene per day and 30 men randomized to the placebo arm, all of whom were diagnosed with incident non-small-cell lung carcinoma during the course of the trial and subsequently underwent radical pulmonary resection. In normal-appearing bronchial epithelium, positive staining for cyclin D1 was observed in 23% of cases in the beta-carotene group and 0% of cases in the placebo group (based on only 3 of 13 versus 0 of 11 cases staining positively, however; P = 0.04), with no differences in expression noted in lung tumor tissue (P = 0.48). There were no statistically significant differences in Ki67 expression in normal or cancerous lung tissue between intervention groups, although a small increase in staining in tumors was noted among cases in the beta-carotene versus placebo group (88% versus 71% of cases stained positive, respectively; P = 0.13). Contrary to expectation, beta-carotene supplementation had no apparent effect on retinoic acid receptor-beta expression. These findings suggest that male smokers supplemented with beta-carotene may have had an increased risk of lung cancer due to aberrant cell growth, although our results are based on a relatively small number of cases and require confirmation in other completed trials of beta-carotene supplementation.

Topics: Aged; alpha-Tocopherol; beta Carotene; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Cocarcinogenesis; Cyclin D1; Cytochromes; Dietary Supplements; Double-Blind Method; Humans; Ki-67 Antigen; Lung; Lung Neoplasms; Male; Middle Aged; Multicenter Studies as Topic; Neoplasm Proteins; Randomized Controlled Trials as Topic; Receptors, Retinoic Acid; Retrospective Studies; Smoking

In this study, we examined oxidative stress and B vitamins status in non-small cell lung cancer (NSCLC) patients at different stages. NSCLC patients were divided into 2 groups, stage III (IIIA + IIIB, n = 27) and stage IV (n = 23). A total of 16 healthy control subjects were included for comparison. Plasma levels of alpha-tocopherol, beta-carotene, vitamin C, Se, Cu, Zn, reduced glutathione (GSH), oxidized glutathione (GSSG), lipid oxidation and the activities of glutathione peroxidase (GPX), superoxide dismutase (SOD), catalase, and xanthine oxidase (XO) were determined for evaluating oxidative status in these subjects. B vitamins (B(1), B(2), B(6), B(12), folate) in blood and plasma ghrelin level in these subjects were analyzed. Results showed that plasma level of ghrelin and lipid oxidation in NSCLC patients were significantly greater than control groups (P < 0.05). The activity of GPX, SOD, or catalase was significantly reduced, but XO activity was significantly elevated in NSCLC patients (P < 0.05). Plasma level of GSH was significantly lower, but GSSG level was significantly increased in NSCLC patients (P < 0.05). Vitamins B(2) and B(6) levels in red blood cells (RBC) from NSCLC patients were significantly lower (P < 0.05), and both were negatively correlated with plasma ghrelin. The correlation coefficients were -0.788 and -0.752, respectively. These data suggest that plasma GSH level may be a proper biomarker for evaluating oxidation status for NSCLC patients. RBC levels of vitamins B2 and B6 were reduced in NSCLC patients; thus, the importance of vitamins B(2) and B(6) for NSCLC patients could not be ignored.

Topics: Adult; Aged; Aged, 80 and over; alpha-Tocopherol; Ascorbic Acid; beta Carotene; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Case-Control Studies; Catalase; Erythrocytes; Female; Ghrelin; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Health Status; Humans; Lipid Peroxidation; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Nutritional Status; Oxidation-Reduction; Oxidative Stress; Superoxide Dismutase; Vitamin B Complex; Xanthine Oxidase

Recent findings of an inverse association between beta-cryptoxanthin and lung cancer risk in several observational epidemiologic studies suggest that beta-cryptoxanthin could potentially act as a chemopreventive agent against lung cancer. However, the biological activity of beta-cryptoxanthin and molecular mechanism(s) by which beta-cryptoxanthin affects lung tumourigenesis have not been studied. In the present study, we found that beta-cryptoxanthin inhibited the growth of A549 cells, a non-small-cell lung cancer cell line and BEAS-2B cells, an immortalized human bronchial epithelial cell line in a dose-dependent manner. beta-Cryptoxanthin suppressed the protein levels of cyclin D1 and cyclin E, up-regulated the cell cycle inhibitor p21, increased the number of lung cancer cells in the G1/G0 phase and decreased those in the S phase of the cell cycle. Consistent with inhibition of the lung cancer cell growth, beta-cryptoxanthin induced the mRNA levels of retinoic acid receptor beta (RARbeta) in BEAS-2B cells, although this effect was less pronounced in A549 cells. Furthermore, beta-cryptoxanthin transactivated RAR-mediated transcription activity of the retinoic acid response element. These findings suggest a mechanism of anti-proliferative action of beta-cryptoxanthin and indicate that beta-cryptoxanthin may be a promising chemopreventive agent against lung cancer.

Topics: Anticarcinogenic Agents; Base Sequence; beta Carotene; Bronchi; Carcinoma, Non-Small-Cell Lung; Cell Division; Cryptoxanthins; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Luciferases; Lung Neoplasms; Molecular Sequence Data; Receptors, Retinoic Acid; Respiratory Mucosa; Up-Regulation; Xanthophylls